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Hepatitis C virus early kinetics and resistance‐associated substitution dynamics during antiviral therapy with direct‐acting antivirals
Author(s) -
Perpiñán Elena,
CaroPérez Noelia,
GarcíaGonzález Neris,
Gregori Josep,
González Patricia,
Bartres Concepción,
Soria Maria Eugenia,
Perales Celia,
Lens Sabela,
Mariño Zoe,
Londoño María Carlota,
Ariza Xavier,
Koutsoudakis George,
Quer Josep,
GonzálezCandelas Fernando,
Forns Xavier,
PérezdelPulgar Sofía
Publication year - 2018
Publication title -
journal of viral hepatitis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.329
H-Index - 100
eISSN - 1365-2893
pISSN - 1352-0504
DOI - 10.1111/jvh.12986
Subject(s) - viral quasispecies , hepatitis c virus , medicine , virology , combination therapy , viral load , virus , hepatitis c
Summary The emergence of resistance‐associated substitutions (RASs) can compromise the high efficacy of direct‐acting antivirals (DAAs). Little is known about RASs selection at very early time points during DAA treatment. Therefore, we analyzed the potential emergence of RASs immediately after therapy initiation. Samples of 71 patients treated with different DAAs were collected at baseline, during therapy (hours 4 and 8; days 1‐7; weeks 2‐4) or until target not detected. HCV‐RNA levels were determined by qPCR, and RASs were detected by deep sequencing. Sixty‐three (89%) patients achieved a sustained virological response (SVR), 7 (10%) relapsed, and 1 (1%) experienced a breakthrough. Almost all non‐SVR (7/8, 88%) showed RASs either at baseline or relapse. High‐frequency RASs detected at baseline (Y93H and L159F+C316N) remained detectable at early time points during therapy and reappeared as most prevalent substitutions at relapse. Conversely, emergent RASs at relapse (Q80R, D168E/V, R155K and L31V) were not observed during the first hours‐days, before HCV‐RNA became undetectable. HCV‐RNA decay and genetic evolution of the quasispecies followed a similar pattern during the first hours of therapy in SVR and non‐SVR patients. In conclusion, the absence of early RASs selection and the similar dynamics of HCV kinetics and quasispecies in SVR and non‐SVR patients after therapy initiation suggest that RASs selection may occur at later stages in the remaining reservoir, where viral populations persist hidden at very low replication levels. Nevertheless, we cannot completely exclude very early selection, when RASs are present below the sensitivity limit of deep sequencing.

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